Journal of Clinical Medicine Review Revisiting Inflammatory Bowel Disease: Pathology, Treatments, Challenges and Emerging Therapeutics Including Drug Leads from Natural Products Karma Yeshi 1, Roland Ruscher 1, Luke Hunter 2, Norelle L. Daly 1 , Alex Loukas 1 and Phurpa Wangchuk 1,* 1 Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns QLD 4878, Australia; [email protected] (K.Y.); [email protected] (R.R.); [email protected] (N.L.D.); [email protected] (A.L.) 2 School of Chemistry, University of New South Wales (UNSW), Sydney NSW 2052, Australia; [email protected] * Correspondence: [email protected] Received: 14 March 2020; Accepted: 20 April 2020; Published: 28 April 2020 Abstract: Inflammatory bowel disease (IBD) is a chronic and life-long disease characterized by gastrointestinal tract inflammation. It is caused by the interplay of the host’s genetic predisposition and immune responses, and various environmental factors. Despite many treatment options, there is no cure for IBD. The increasing incidence and prevalence of IBD and lack of effective long-term treatment options have resulted in a substantial economic burden to the healthcare system worldwide. Biologics targeting inflammatory cytokines initiated a shift from symptomatic control towards objective treatment goals such as mucosal healing. There are seven monoclonal antibody therapies excluding their biosimilars approved by the US Food and Drug Administration for induction and maintenance of clinical remission in IBD. Adverse side effects associated with almost all currently available drugs, especially biologics, is the main challenge in IBD management. Natural products have significant potential as therapeutic agents with an increasing role in health care. Given that natural products display great structural diversity and are relatively easy to modify chemically, they represent ideal scaffolds upon which to generate novel therapeutics. This review focuses on the pathology, currently available treatment options for IBD and associated challenges, and the roles played by natural products in health care. It discusses these natural products within the current biodiscovery research agenda, including the applications of drug discovery techniques and the search for next-generation drugs to treat a plethora of inflammatory diseases, with a major focus on IBD. Keywords: inflammatory bowel diseases; ulcerative colitis; Crohn’s disease; small molecule drugs; biologics; anti-inflammatory; natural products drugs 1. Introduction Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn’s disease (CD). UC was first described in 1859 [1], and CD in 1932 [2]. Both UC and CD are chronic and debilitating diseases without a real cure. As of 2017, 6.8 million IBD cases were reported globally, with an increase in age-standardized prevalence rates from 79.5 per 100,000 population in 1990 to 84.3 per 100,000 population in 2017 [3]. More than 1.6 million people in the United States [4], 250,000 in the United Kingdom [5], 260,000 in China [6], and 85,000 in Australia are affected by IBD [7]. Over the past few decades, IBD was most dominant in the western world as both the rate of incidence and prevalence were higher compared to developing countries. Recently, however, IBD incidence has increased rapidly in many Asian countries [5] with consistently rising trends, particularly in Japan, Korea, Hong Kong, J. Clin. Med. 2020, 9, 1273; doi:10.3390/jcm9051273 www.mdpi.com/journal/jcm J. Clin. Med. 2020, 9, 1273 2 of 39 and mainland China [8]. In Asia, males between the ages of 20 to 39 years are affected more by CD, and there is also a higher prevalence of ileocolonic CD, which is not the case in western countries [9–11]. There is a lack of national registries in many developing Asian, African, and Latin American countries and, therefore, much less is known about the incidence and prevalence of IBD. IBD causes substantial morbidity [12] and heavy productivity losses [13,14]. The increasing trends in the rate of incidence and prevalence of IBD and lack of a cure or effective long-term treatment options have resulted in a substantial financial burden to the healthcare system worldwide [3,15,16]. When Park et al. [17] analyzed healthcare costs for 52,782 IBD patients in the United States on a per-year basis, IBD patients incurred a greater than 3-fold higher direct cost of care compared to non-IBD patients (US $22,987 vs. US $6956 per-member per-year paid claims) and more than twice the out-of-pocket costs (US $2213 vs. US $979 per-year reported costs), with all-cause IBD costs rising since 2013. Moreover, IBD patients have to bear significantly higher cost associated with the time they spend on their healthcare, unlike non-IBD patients. Similarly, Australia spends approximately AU $100 million per annum for IBD related hospitalization costs, more than AU $380 million related to productivity loss, and an additional $2.7 billion for other financial and economic costs [18]. The financial burden for IBD is highest during the first year of diagnosis, followed by a more stabilized cost pattern by seven to eight years after diagnosis. However, treatment costs tend to rise again after this period [17]. The fluctuation in the financial burden can be attributed to either age-related or healthcare-related factors, including inconsistent access to health care, support and education, and insecure funding for IBD-treating hospitals. Treatments (biologics, opioids, or steroids), emergency department use, and health care services associated with relapsing disease, anemia, or mental health comorbidity are some of the critical factors that may cause financial burden to all countries until a cure for IBD is established [17]. Despite the huge financial cost to the health care system and the morbidity burden faced by many countries, effective treatments for IBD remain elusive for many reasons. Recent reviews by Jeong et al. [19], Neurath [20], Kaplan [15], Ananthakrishnan [21], and Ruel et al. [22] highlight the epidemiology and risk factors for IBD, associated global health burden, and current therapeutic targets. There is, however, limited review coverage of the role of natural products in treating IBD. This current scoping review explores the causative factors, challenges in current treatment options, and the status of drug discovery from natural products for combating IBD. 2. Diagnosis and Pathophysiology of Inflammatory Bowel Disease Both CD and UC show heterogeneity in many clinical and pathological features. They are distinguishable by their location and nature of inflammation (Figure1). Unlike UC, which attacks colonic mucosa, CD can affect any part of the gastrointestinal (GI) tract [23]. Both conditions share clinical features like extra-intestinal manifestation, but hematochezia and passage of mucus or pus are common only in UC. Fistulas, perianal disease, colonic and small bowel obstruction is common in CD. Cryptitis and crypt abscesses are observed in both UC and CD, while crypt architecture is more distorted in the case of UC [24]. Both UC and CD show relapsing intestinal inflammation. Intermediate colitis (IC) sometimes does not present distinct clinical features of either UC or CD, particularly in colectomy specimens, rendering it hard to distinguish UC from CD. Although IC is not a unique disease or distinct clinical entity, it accounts for around 10% of the total IBD cases involving the colon [25], and this figure has not changed over the last 30 years [26]. Currently, IC is usually diagnosed when a distinction between UC and CD becomes difficult. A standard positive diagnostic test for IC is not yet available. J. Clin. Med. 2020, 9, 1273 3 of 39 J. Clin. Med. 2020, 9, x FOR PEER REVIEW 3 of 39 Figure 1.1. DiDifferentfferent typestypes ofof InflammatoryInflammatory BowelBowel diseases.diseases. ((AA)) UlcerativeUlcerative colitis:colitis: proctitis,proctitis, left-sidedleft-sided colitis, and extendedextended colitis;colitis; ((B)) Crohn’sCrohn’s disease:disease: Ileocecal Crohn’s disease, Crohn’s colitis,colitis, andand Fistulising Crohn’s disease. Red indicates area of inflammation.inflammation. 2.1. Ulcerative Colitis 2.1. Ulcerative Colitis UC causes inflammationinflammation and ulceration of the inner lining of the colon and rectum (the large bowel). There is no gender predominance in UC, and the peak age of disease onset is between ages 30–40 years [[27].27]. Symptoms usually include diarrhea, abdominal pain, fatigue, loss of appetite and weight, and anemia. The severity of symptoms depen dependsds upon how much of the colon is aaffectedffected or inflamed.inflamed. Inflammation Inflammation in UC is non-specificnon-specific and maymay occur in the rectum (proctitis), left semicolon (left-sided(left-sided colitis)colitis) oror entireentire coloncolon (extensive(extensive colitiscolitis oror pancolitis)pancolitis) (Figure(Figure2 )[2) 28[28].]. J. Clin. Med. 2020, 9, 1273 4 of 39 J. Clin. Med. 2020, 9, x FOR PEER REVIEW 4 of 39 Figure 2. TypesTypes of ulcerative colitis and diagnosis. Currently, there is no ‘gold‘gold standard’standard’ test toto diagnosediagnose UCUC [[29].29]. Diagnosis of UC relies on test results obtained by colonoscopy, histopathology, bloodblood testing, fecal examination, and radiological studies [30]. [30]. Patients Patients diagnosed diagnosed with with UC UC at at an an ol olderder age are at lower risks of colectomy than those diagnosed at a younger age (below 16 years) [[30].30]. According to a meta-analysis of population-based cohort studies, the risk of developing colorectal canc cancerer is 2.4-fold higher in patients with UC, and the risk is higher in males than females and for those diagnosed with UC and extensive colitis at a young age [31]. [31]. The pathogenesis of UC and CD is considerably distinct from each other. The change in luminal microbial diversity diversity (dysbiosis), (dysbiosis), impairment impairment of of epithelial, epithelial, and and mucus mucus layer layer barrier barrier via via disruption disruption of tightof tight junctions junctions are arestrongly strongly implicated implicated in the in pathog the pathogenesisenesis of UC.